The present invention relates to methods for producing N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine (its general name is nateglinide and hereinafter referred to as nateglinide) that is useful as a therapeutic agent for diabetes. More specifically, it relates to industrially beneficial methods for crystallization of nateglinide.
It is known that nateglinide is useful as a therapeutic agent for diabetes because it effectively lowers blood glucose by oral administration (Japanese Patent Publication No. Hei 4-15221).
It is also known that nateglinide has crystal polymorphs and H-type crystals are useful among them (Japanese Patent No. 2508949).
On the other hand, in order to synthesize nateglinide, when trans-4-isopropylcyclohexylcarbonyl chloride and D-phenylalanine were reacted in a mixed solvent of ketone solvent and water, and H-type crystals of nateglinide were precipitated from the reaction mixture in accordance with the method described in Japanese Patent No. 2508949, the synthesized crystals were small and it took a long time to complete the separation by filtration when the filtering device available on the industrial scale was used. Therefore, it was found that the above-described method was not practical